The leukotriene cascade of arachadonic acid is a key mechanism in many inflammatory and allergic disease states. The dihydroxy fatty acid leukotriene B.sub.4 (LTB.sub.4), produced by this cascade, is a key pro-inflammatory mediator. LTB.sub.4 stimulates adhesion of circulating neutrophils to vascular endothelium, directs their migration toward sites of inflammation, and induces secretion of further inflammatory mediators. (For reviews see R. A. Lewis et al, N. Engl. J. Med. 1990, 323, 645-655 and M. -Q. Zhang, Curr. Med. Chem. 1997, 4, 67-78.) Leukotriene-A.sub.4 hydrolase (LTA.sub.4 -hydrolase) (EC 3.3.2.6) is an enzyme that catalyses the final and rate limiting step in the synthesis of LTB.sub.4. Inhibition of LTA.sub.4 hydrolase selectively blocks the biosynthesis of LTB.sub.4 which may provide an advantage over current inhibitors, such as those of 5-lipoxygenase, that block earlier in the leukotriene cascade and as a result are less selective.
Disease states associated with elevated levels of LTB.sub.4, and which are therefore considered to be responsive to inhibition of intracellular leukotriene-A.sub.4 hydrolase activity include asthma, inflammatory bowel disease, psoriasis and arthritis.
Peptidomimetic compounds, such as bestatin, captopril and kelatorphan exhibit LTA.sub.4 hydrolase inhibitory activity against isolated enzyme (T. D. Penning et al, Biorg. Med. Chem. Lett., 1995, 5, p2517-2522). However, these compounds are unable to effectively penetrate cells and hence have little anti-inflammatory activity. There is therefore a need in the art for compounds which are capable of inhibiting intracellular LTA.sub.4 hydrolase activity.